Oroshnik



Sept. 9, 1952 w. OROSHNIK 2,510,184

2AMINO-4-DIALKYLAMINOETHOXYPYRIMIDINES Filed Nov. 7, 1950 2 SI-IEETSSHEET 1 T: qi. TH E...

INVENTOR WILL/AM OROSHN/K.

ATTORNE Sept. 9, 1952 w. ORO SHNIK 2,610,184

2-AMINO-4-DIALKYLAMINOETHOXYPYRIMIDINES Filed Nov. 7, 1950 z srmsw-smw 2' INVENTOR a v a 6 ATTORN W/L IAM Geog/mm.

Patented Sept. 9, 1952 UNITED STATES PATENT OFFICE; i

2-AMINO-4-DIALKYLAMINOETHOXY- PYRIMIDINES William Oroshnik, Plainficld, N. I, assignor to Ortho Pharmaceutical Corporation, a corporation of New Jersey Application November 7, 1950, Serial No.'194 ,559

4 Claims. (01. 260-2534) in which R and R are each an aliphatic radical which may be isopropyl, secondary butyl, or normal butyl.

A number of derivatives of isocytosine have been prepared and studied for various pharmaceutical and medicinal uses but it is believed that the particular derivatives of isocytosine with which this invention is concerned are new substances. It is also believed the ability of these substances to stimulate contractions of the uterus has not been known heretofore.

The derivatives of isocytosine which embody this invention may be used as such to stimulate contractions of the uterus. They may also be used as in the form of salts of the isocytosine derivatives with organic or inorganic acids and since the said derivatives are basic in character, they may be readily converted into salts having substantially more solubility in water than the free bases. Salts such as the succinate, maleate, tartrate, lactate, fumarate and the like are preferred, but salts of simple low-molecular weight aliphatic organic acids as well as salts of the free bases with inorganic acids, may be readily prepared from the free bases and are highly efiective therapeutically.

The new and novel derivatives of isocytosine to which the present invention is directed have considerable value which renders their use as pharmaceutical products highly advantageous either alone or with known pharmacological products. The ability of these novel substances to stimulate contractions of the uterus has been shown by a number of experiments in which a salt of the isocytosine derivative was added to a. bath of nutrient solution having a stripof albino rat uterine tissue suspended therein. 'A continuous kymographic record was made of contractions of the uterine strip. before and after addition to the bath of a salt of an isocytosine derivative. Additional derivatives or isocytosine which are homologues of 2-amino-4-dialkylaminoethoxypyrimidines specifically mentioned before as having therapeutic value were also tested in the same way to determine their effect on contractions of the uterus. The sesquisuccinates of the following compounds were tested for their pharmacological property of stimulating contractions of the uterus:

Compound I2 amino 4 di n butylaminoethoxypyrimidine Compound II2 amino 4 diisopropylaminoethoxypyrimidine y 1 Compound III-2 amino 4 dimethylaminoethoxypyrimidine Compound IV2 amino 4 diethylaminoethoxypyrimidine Q CompOundV-Z amino 4 diethylaminoethoxy-fi-methylpyrimidine' The following procedure was employed in testing the eifect of compounds I-V on a rat uterus: A female albino rat weighing from 150- 300 milligrams was killed by a blow on the head and the uterus was removed. A strip of the uterine tissue was suspended in a (ac/bath of an aerated Ringer-Locke solution. Onewend of the uterine strip was maintained in a stationary position and the other end was attached to a lever which made contact with a kymograph and continuously recorded contractions. After a short period of immersion in the bath, the strip of uterine tissue was contracting rhythmically and normally, and at this point a sesquisuccinate of an isocytosine derivative to be tested for itsreifect on contractions of uterine tissue was added to the bath. Figures 1-7 are kymographic records of contractions of the strip of uterine tissue before and after addition to the bath of the compounds to be tested. Normal contractions are recorded in the figures up to the point designated a and at this time a portion of the compound to be tested was added to the bath. The portion of the figures between letters a and b represents a record of contractions after addition to the bath of the compound being tested. The letter I) in the figures designates the time at which the bath containing the compound being tested was removed and replaced by a nutrient bath containing no isocytosine derivative. That portion of Figures 1-7 after the letter b represents contractions as they return to normal and after the uterine strip is no longer in contact with a compound being tested for its efiect on contractions of uterine tissue.

Figures 1,2, and 3 show the effector the addition of 1, 5, and 10 milligrams, respectively, of the sesquisuccinate salt of compound I to the bath.

Figures 4, 5, and 6 and '7 show the effect of they addition of 10 milligrams of compounds II, III, IV, and V, respectively, to the'bath. Figure I dissolved sodium hydroxide were added with stirshows the addition of 1 milligram of the sesqui'succinate of compound I to the bath produceda substantial increase in amplitude of contractions, a J

slight increase in frequency, and a slight increase in tonus of the uterine muscular tissue.

Figure 2 shows a greater increase in tonus upon the addition of 5 milligrams of thesesquisuccinate salt of compound'I to the bath. The addition of milligrams of .the sesquisuccinate salt of compound I to the bath produced a'reaction of the uterine tissue substantially corresponding to. a state of tetanic contraction. Figure 4 shows the, addition of .10 milligrams of the sesquisuccinatesalt of compound II to the bath produced a marked increase in. amplitudeof contractions and a slight, increase in tonus of the uterine muscular tissue. Figures 5, 6 and 7 show only slight effects on the uterine tissue result from the addition of the sesquisuccinate salts of compounds III, IV, and V, to the bath. Figure 5 shows the addition or" 10 milligrams of the sesquisuccinate salt of compound'III produced a slight decrease in amplitude of contractions, and Figures 6 and '7 show the addition of 10 milligrams of the sesquisuccinate salts of compounds IV and V, res spectively, to the bath, produced a slight increase in amplitude of contractions and a slight increase in tonus of the uterine muscular tissue.

Tonus is a natural property of muscle and is a measure of degree of contraction independent of external influences. The degree of contraction produced'by a stimulant depends upon the level of tonus, and, therefore, some investigators have defined tonus as the resistance offered to extension. 1

Amplitude may be defined as the height of a contraction wave measured from the base level to the peak of 'the'wave; base level being the average-lower level of the contractions.

Frequency is the number of contraction waves in a unit time period. r Derivatives of isocytosine such as 2-amino--i dialkylaminoethoxypyrimidines'may be prepared ring. At this point two layers were formed and th organic layer was decanted, dried over anhydrou's potassium carbonate, and the solvents, benzene and xylene, were removed by distillation. The residue in the distillation flask was distilled at a temperature of l-l56 C. and a pressure of 0.02 mm. of mercury. Two hundred and ten parts of 2- amino-4-di-n-butylaminoethoxypyrimidine were obtained. The. picrate of thismaterial. wasprepared and had a melting point f l-i9-l49.5*C. The pure compound is soluble in mostv organic compounds and insoluble in water. Ase'squisuce cinate of the free vbaseiw'as prepared as follows: 7.1 gramsof the base and 4.75 grams of succinic acid were dissolved in 9 cc. of hot absolute alcohol and then dilutedwith 18 cc. of acetone. A white crystalline material precipitated on cooling this solution. The precipitate was removed b filtering and recrystallized from a mixture of absolute alcohol and acetone. The recrystallized material had a melting point of 111-112 C. The crystal line salt had the following formula:

What is claimed is: l. A compound having the structural formula R NHiO COCHzCH2N N CH REFERENCES CITED The following references are of record in the file of this patent:

Sutherland et al.:

J. Org. Chem. 14, 235-238 (194.9 ,1 

1. A COMPOUND HAVING THE STRUCTURAL FORMULA 